This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Tobacco related lung diseases, including chronic obstructive pulmonary disease (COPD) with and without emphysema, are major causes of lung-related disability and death worldwide. The etiology of worsening of respiratory sumptoms in patients with COPD, and the phenotype of these subjects that require special medical attention, are probably heterogeneous and certainly poorly understood. In a longitudinal cohort study, we have shown that approximately one half of subjects with severe COPD (GOLD stage III, and IV), had at least one emergency center visit and/or hospital admission for respiratory failure as compared to no need for urgent medical care in normal controls or subjects with mild COPD (GOLD stage 0-11) in 23 months. Surprisingly however, we found similar annual symptomatic respiratory virus infection rates in severe COPD subjects as compared to controls. Thus, although patients with severe COPD have comparable documented viral infections, they still utilize more medical care resources than controls. One possible explanation is that the immune response to the viral infection in patients with COPD differs fromthat of control groups. In support of this idea, our group has rectntly shown that the lung-specific immune phenotype of stable ex-smokers with COPD and emphysema is biased towards T helper type 1 (Th1) immune dysregulation that is not seen in those without the disease. Our proposal will prospectively identify two cohorts of patients 1) ambulatory patients with various stages of COPD, during stable condition and during COPD exacerbation as defined byour operational definition of COPD exacerbation, as upper respiratory tract illness defined by the presence of symptoms of rhinitis or pharyngitis, and/or lower respiratory tract illness defined by increase cough, shortness of breath, sputum production and/or change in sputum color in the presence or absence of fever (temperature 37.7 degrees);where the severity of exacerbation will be graded based on the validated St George''s Respiratory Questionnaire;2) patients admitted to the Texas Medical Center hospitals with COPD exacerbation. We will also study normal controls (smokers and non-smokers). In aim one of this proposal we will characterize our COPD cohort and will prospectively determine the phenotype of subjects to determine if a specific set of physical and functional characteristics can be used to distinguish sujbects with frequent COPD exacerbation. A special emphasis will be placed on studies that willdefine the role of concurrent emphysema, in our study subjects. The role of congestive heart failure, and liver and kidney dysfunction will be investigated as potential contributing factors in subjects with frequent exacerbation. In the second and third aims of the proposal we will determine the mechanisms for the viral and non-viral mediated T cell responses that may contribute to frequent exacerbation and decline in lung function of this cohort.